Dynamics-Function Relationships in Cytochromes c

描述(由申请人提供)：铁原卟啉IX(Heme)的氧化/还原(氧化还原)化学是许多基本生物过程的中心，包括能量传递、氧化还原催化、传感和信号传递。虽然已经有很多关于血红素蛋白结构-功能关系的研究，但关于血红素蛋白动力学与功能之间的关系却鲜有人关注。此外，我们对血红素蛋白的氧化还原相关的生物物理性质如何影响电子转移的理解还不够深入。在这个项目中，我们将研究细胞色素c(Cytc)的结构迁移率如何调节血红素的氧化还原功能。细胞色素C是一种普遍存在的蛋白质，具有一系列与氧化还原相关的功能。它们的特征是血红素与多肽的共价结合方式，通常是在Cys-X-X-Cys-His基序中的两个Cys残基上。相对于细胞色素b(-130到+390 mV对NHE)，细胞色素C跨越了更大的电位范围(从-412到+450 mV vs.NHE)，它们具有相同的血红素辅助因子，但缺乏与多肽的共价键。到目前为止，对电势范围的这种变化以及血红素c获得极低电势的能力还没有做出解释。血红素C与多肽的结合方式赋予了多肽独特的结构和动力学性质。本文描述的结构和氧化还原电位数据提供了一个引人注目的案例，即血红素c的特定性质在氧化还原电位调节中发挥着重要的间接作用；我们认为c-血红素基序的局部结构和波动调节铁配体相互作用，从而调节氧化还原电位。此外，我们还将探索c-血红素结合对原卟啉IX大环自身构象的控制如何有助于氧化还原电位的调节。 细胞色素在线粒体、细菌、叶绿体以及许多古生物的能量传递中起着至关重要的作用。这样的过程是活性氧物种(ROS)的重要来源，而ROS是与衰老相关的疾病的主要促成因素。为了全面了解导致衰老和细胞死亡的事件，以及一系列疾病的发生和发展，必须了解细胞内氧化还原化学的基本原理。因此，阐明控制生物氧化还原化学的基本机制对生物医学科学和人类健康具有重要意义。

DESCRIPTION (provided by applicant): Oxidation/reduction (redox) chemistry of iron-protoporphyrin IX (heme) is central to many fundamental biological processes including energy transduction, redox catalysis, sensing, and signaling. Although there have been many studies of structure-function relationships in heme proteins, the relationship between heme protein dynamics and function has received little attention. In addition, our understanding of how redox- dependent biophysical properties of heme proteins impact electron transfer is not well developed. In this project, we will investigate how cytochrome c (cyt c) structural mobility modulates heme redox function. Cyts c are ubiquitous proteins displaying a range of redox-related functions. They are characterized by the covalent means of heme attachment to the polypeptide, usually to two Cys residues in a Cys-X-X-Cys-His motif. Cyts c span a larger range of potentials (from -412 to +450 mV vs. NHE) relative to cyts b (-130 to +390 mV vs. NHE), which have the same heme cofactor but lack covalent bonds to the polypeptide. To date, an explanation for this variation in range of potentials, and the ability of heme c to access extremely low potentials, has not been made. The means of attachment of heme c to the polypeptide impart on it unique structural and dynamical properties. Data on structure and redox potential described herein present a compelling case that the specific properties of heme c play an important if indirect role in redox potential tuning; we propose that the local structure and fluctuations about the c-heme motif tune iron-ligand interactions and thus redox potential. In addition, we will explore how control of the conformation of the protoporphyrin IX macrocycle itself by the c-heme attachment contributes to redox potential tuning. Cytochromes play vital roles in energy transduction in mitochondria, bacteria, and chloroplasts, as well as many archaea. Such processes are a significant source of reactive oxygen species (ROS), which are a major contributing factor to diseases associated with aging. To develop a complete understanding of events contributing to aging and cell death, and to the development and progression of a range of diseases, the fundamentals of redox chemistry in the cell must be understood. Elucidating basic mechanisms controlling biological redox chemistry is therefore of fundamental importance to biomedical sciences and human health.